1. Field of the Invention
The invention pertains to GPNA oligonucleotides, and in particular to EGFRAS GPNA oligonucleotides, which has utility in treating malignant tumors.
2. Description of Related Art
Among other cancers, head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy that is difficult to treat with conventional therapies. Despite significant advances over the past 3 decades, current treatment modalities including surgery, radio- and chemotherapy have not improved five-year survival rates in HNSCC patients. Molecular signatures of HNSCC—indeed, all—malignancies is a topic of great current interest.
The Epidermal Growth Factor Receptor (EGFR) has emerged as a promising molecular target in the past decade or so, and in particular EGFR is upregulated in the majority of HNSCC tumors, so it is not surprising that preclinical model inhibition of EGFR has resulted in tumor inhibition. Notably, increased EGFR levels in HNSCC tumors have been associated with advanced stage, large tumor size, invasion, decreased survival and poor prognosis. Notwithstanding this preclinical promise, clinical trials using agents that inhibit EGFR activation and signaling have demonstrated limited antitumor efficacy. Another popular approach to target EGFR is to downmodulate its expression levels. Antisense DNA sequences that bind target DNA or mRNA inhibiting transcription or translation are highly effective in inhibiting HNSCC. However, DNA based agents are prone to nuclease degradation and hence have short half-lives in plasma, and RNA- and/or DNA-based antisense agents are not cell-permeable, necessitating the finding of a carrier or effective modification before the agent can pass the cell membrane. Heretofore, then, the dual or triple goals of enzymatic stability, cell-permeability and antitumor effects have not been achieved by methods and agents known prior to the present invention.
Therefore, a need remains for a way to administer antisense agents such as EGFR Antisense (EGFRAS)—whether as complete genes or as oligonucleotides—that are resistant to nucleases and proteases and thus can be given to patients systemically, i.e., parenterally or via other appropriate systemic administration, to combat HNSCC and other malignancies for which such treatment is indicated.